To study complex organs and tissues, such as brain and tumor, it is necessary to understand its integrated 3-D structure and fine molecular details throughout the whole tissue. Current methods, exemplified by array tomography or serial block-face scanning electron microscopy can provide sub-cellular fine details, but involve prohibitively inefficient and damaging mechanical sectioning and reconstruction. Optical sectioning techniques combined with tissue clearing methods have been developed, in which light-scattering is reduced to increase the depth at which tissue can be imaged. While these methods can bypass laborious mechanical sectioning and reconstruction processes, they are not compatible with immunostaining/molecular phenotyping. What is needed is a technology for the preparation of biological tissue for microscopic analysis that maintains the 3-D integrity of the tissue and of the sub-cellular structures therein, while also making biomolecules within the tissue e.g., proteins, lipids, steroids, nucleic acids, and small molecules, accessible for labeling with molecular probes at deeper regions in the tissue. The present invention addresses these and other issues.